Method for crystallizing maleic acid salt of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline

ABSTRACT

A process for simply and easily crystallizing a maleate salt of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (enalapril) having a high quality out of an aqueous liquid, which comprises mixing an aqueous liquid having a pH of not less than 4 and containing N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, maleic acid and a base with an amount of an acid sufficient to convert substantially all the base into a neutral salt.

This application is a 371 of PCT/JP99/03872 filed Jul. 19, 1999.

TECHNICAL FIELD

The present invention relates to a process for economicallyadvantageously crystallizing a maleate salt ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (hereinafteralso referred to as “enalapril”) of the formula (I):

on a commercial scale in a high quality and a high yield to therebypurify the maleate salt. TheN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt(enalapril maleate) is a compound very useful as an antihypertensiveagent.

BACKGROUND ART

A process for crystallizing a pharmacologically acceptable salt ofenalapril (I), particularly enalapril maleate that the pharmacologicallyacceptable salt is maleate salt, is disclosed, for example, in U.S. Pat.No. 4,442,030, U.S. Pat. No. 4,374,829 and U.S. Pat. No. 5,359,086wherein the process is conducted by recrystallization from an organicsolvent such as acetonitrile. However, it is assumed that a trace amountof the organic solvent is unavoidably introduced into the final product,thus imparting undesirable characteristics to enalapril maleate which istaken in by a human being. Accordingly, the use of organic solventsshould be avoided. From such a point of view, the use of an aqueousliquid would produce favorable results.

As to a process for taking enalapril maleate out of an aqueous liquid inthe form of crystals, for example, Journal of Organic Chemistry, Vol.53, 836-844(1988) discloses a process wherein enalapril maleate having asmall content ofN-(1(R)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate whichis an optical isomer that the configuration of carbon atom to whichethoxycarbonyl group bonds is different from enalapril, is obtained byrecrystallizing enalapril maleate from water. However, no detail ofprocedure, yield, purification effect and so on is disclosed therein.

Also, U.S. Pat. No. 4,374,829 discloses a process for obtaining anenalapril salt by converting enalapril to its pharmacologicallyacceptable salt in water followed by an operation such as evaporation ofwater or freeze drying. However, the process requires a long time in itsoperation and accordingly have problems such as waste of time, loweringof productivity, waste of vast energy and complication of operation, sothe process has many problems to be solved in production on a commercialscale.

Thus, it has been desired to provide a process for economicallyadvantageously crystallizing enalapril maleate having a high qualitydirectly from an aqueous liquid in a high yield.

The maleate salt of the enalapril (I) can be obtained in general bymixing enalapril and maleic acid in a suitable solvent, preferably anaqueous liquid, to produce the enalapril maleate and obtaining it in theform of crystals after forming a slurry with a high concentration byconcentration, freeze drying or the like. However, in case of obtainingthe crystals directly from the above aqueous liquid without applying anyspecial procedure, it is difficult, from the point of solubility, toachieve a large amount of crystallization. In particular, in case ofpurification by a recrystallization method wherein enalapril maleate isonce dissolved in an aqueous liquid and then recrystallized, it isparticularly difficult to raise the amount of crystallization owing tosolubility characteristics of enalapril maleate. For increasing theamount of crystals deposited in this recrystallization method, it isrequired to make the difference in the amount of dissolution largebetween at the time of forming the solution and at the time ofcrystallization. For example, in case of the cooling crystallization, alarge amount of crystallization is not achieved since the change insolubility of enalapril maleate based on the difference in temperatureis relatively small. Thus, it is necessary to combine it with aconcentrating crystallization so as to decrease the amount of motherliquor to thereby increase the amount of crystals deposited. However,such an operation requires a long time and, therefore, it is not anadvantageous process from the viewpoints of waste of time, lowering ofproductivity, waste of vast energy and complicated operation. Further,since the solubility of enalapril maleate is generally low even at hightemperatures, the amount of the solution becomes large relatively andthis brings about disadvantages such as enlargement of dissolutionequipment, lowering of productivity and increase of waste water.Therefore, the application of the process to a commercial scaleproduction requires a further improvement. Also, increase in thermalhysteresis through dissolution and concentration operations isunfavorable because it leads to a serious problem such as increase inproduction of impurities. However, no effective means for solving theseproblems has been known.

Also, in case of forming enalapril maleate in a solvent from enalapriland maleic acid and then crystallizing the maleate, there arise problemsthat a diketopiperazine derivative is by-produced and a carboxyderivative contaminates.

Accordingly, it is an object of the present invention to provide asimple and economically advantageous process suitable for industrialproduction wherein enalapril maleate having a high quality is obtainedin a high yield by dissolving enalapril maleate in an aqueous liquid ina high concentration and crystallizing the maleate directly from theresulting solution.

A further object of the present invention is to provide a process forobtaining enalapril maleate having a high quality in a high yield and ahigh efficiency from enalapril and maleic acid.

DISCLOSURE OF INVENTION

The present inventors have found that:

(i) as a manner for obtaining a solution of enalapril maleate dissolvedin an aqueous liquid in a high concentration it is effective to dissolvethe maleate under a condition of a pH of not less than 4 by using abase,

(ii) a large difference in solubility of enalapril maleate is obtainedby mixing the aqueous liquid of pH 4 or higher obtained in (i), in whichenalapril maleate is dissolved in a high concentration, with an acid tolower the pH, preferably to lower the pH to a pH 2 to 3,

(iii) as a consequence, enalapril maleate having a high quality can beeconomically advantageously crystallized in a simple manner in a highyield merely by lowering the pH of the aqueous liquid obtained in (i)without applying any additional procedure, and at that time a saltingout effect based on a neutral salt (particularly inorganic salt)produced by the acid contributes to increase in the amount of crystalsdeposited, and

(iv) by using the process mentioned above, enalapril maleate having alow content of impurities such asN-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline (hereinafter alsoreferred to as “carboxy derivative (III)”) of the formula (III):

is obtained, while suppressing by-production of a diketopiperazinederivative of the formula (II):

Thus, the present invention provides a process for crystallizing amaleate salt ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline of the formula(I):

which comprises mixing an aqueous liquid having a pH of not less than 4and containing N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline(I), maleic acid and a base with a sufficient amount of an acid toconvert substantially all of said base into a neutral salt.

The base changes into a neutral salt by mixing of the aqueous liquidwith an acid, whereby the solubility is lowered to crystallize thecompound (I) as its maleate salt out of the aqueous liquid. Further, theproduced neutral salt contributes to crystallization of the maleate saltby salting out effect. According to the process of the presentinvention, a maleate salt ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (I) having alow content of N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline of theformula (III):

can be obtained, while restraining by-production of a diketopiperazinederivative of the formula (II):

BEST MODE FOR CARRYING OUT THE INVENTION

An aqueous liquid having a pH of at least 4 and containing enalapril,maleic acid and a base can be obtained, for example, by dissolvingenalapril maleate in an aqueous liquid under a condition of a pH of notless than 4. Alternatively, it can also be obtained by dissolvingenalapril and maleic acid respectively in an aqueous liquid. In case ofdissolving enalapril maleate in water, the pH of the resulting solutionbecomes 2 to 3 and, therefore, the pH of the aqueous liquid is usuallyadjusted to a pH of not less than 4 by using a base.

The enalapril (I) and its maleate salt to be used can be prepared, forexample, by a process disclosed in Japanese Patent Publication Kokai No.62-48696, U.S. Pat. No. 4,374,829 and WO99/05164.

The base used for dissolving the enalapril maleate in an aqueous liquidunder a condition of a pH of not less than 4 is not particularlylimited, and can be selected from inorganic bases and organic bases.Examples of the base are, for instance, inorganic bases such ashydroxides, carbonates and bicarbonates of alkali metals or alkalineearth metals, and organic bases such as quaternary ammonium hydroxides.Representative examples of these bases are, for instance, an alkalimetal hydroxide such as sodium hydroxide, potassium hydroxide or lithiumhydroxide, an alkali metal carbonate such as sodium carbonate, potassiumcarbonate or lithium carbonate, an alkali metal hydrogencarbonate suchas sodium bicarbonate or potassium bicarbonate, an alkaline earth metalhydroxide such as magnesium hydroxide or calcium hydroxide, a quaternaryammonium hydroxide such as tetramethylammonium hydroxide,tetraethylammonium hydroxide, tetrapropylammonium hydroxide,tetrabutylammonium hydroxide, tetraamylammonium hydroxide,tetrahexylammonium hydroxide or benzyltrimethylammonium hydroxide, andthe like. Other bases than the above can also be used.

It is advantageous to use bases which are inexpensive and easy to handleand treat waste water and, in addition, which can exhibit a highersalting out effect based on a neutral salt formed when mixed with anacid. For example, preferable are inorganic bases, particularly analkali metal hydroxide such as sodium hydroxide, potassium hydroxide orlithium hydroxide, an alkali metal carbonate such as sodium carbonate,potassium carbonate or lithium carbonate, and an alkali metalhydrogencarbonate such as sodium bicarbonate or potassium bicarbonate.Of these, alkali metal hydroxides, especially sodium hydroxide andpotassium hydroxide, are more preferable. From the viewpoint ofoperability or the like, preferably the inorganic bases are used in theform of an aqueous solution. For example, it is advantageous to use anaqueous solution of an alkali metal hydroxide having a concentration of2 to 20 N, preferably 5 to 20 N. The bases may be used alone or inadmixture thereof.

The base is used in an amount sufficient to adjust the pH of an aqueousliquid containing enalapril and maleic acid to 4 or more, for example,in an amount necessary to dissolve enalapril maleate in an aqueousliquid under a condition of a pH of not less than 4. In general, theamount of the base used is equal to or greater than molar equivalents(acid-base equivalent) of the maleic acid used. In case of an embodimentwherein enalapril maleate is dissolved, the amount is equal to orgreater than molar equivalents of the maleate. However, the use of thebase in an amount necessary to maximize the salting out effect based ona neutral salt formed when mixing with an acid in the subsequent stepcan also be suitably utilized from the viewpoint of increasing theamount of crystals deposited.

From such a point of view, more preferably the pH of the aqueous liquidat the time of dissolution is not less than 5, though the process can bewell practiced if the pH is not less than 4. When the pH of the aqueousliquid is within the above range, it is possible to dissolve enalaprilmaleate in a high concentration. It is unfavorable to raise the pH tomore than necessary at the time of dissolution, since it brings aboutby-production of the carboxy derivative (III) by hydrolysis ofethoxycarbonyl group. Therefore, in general, it is preferable that thepH of the aqueous liquid at the time of dissolution is at most 10,especially at most 8, more especially at most 7.

The aqueous liquid is substantially water, but may be a mixture of waterand an organic solvent contained within a range exerting no badinfluence.

The concentration of enalapril in the aqueous liquid cannot begenerically specified since it varies depending on operationtemperature, kind and amount of the base used, composition of theaqueous liquid, and kind and concentration of a coexisting inorganicsalt, but it can be freely selected within the range capable of forminga uniform solution. In order to increase the amount of crystalsdeposited in the subsequent crystallization step, it is preferable toprepare a solution having a concentration as high as possible. Forexample, the solution can be used at a saturation concentration underoperation conditions such as pH and temperature or in the vicinity ofthe saturation concentration or in the supersaturated state.Practically, the process can be carried out at a high concentration ofat least 10%, preferably at least 20%, more preferably at least 30%.

The concentration of maleic acid is within a range causing no trouble inthe practical operation, wherein maleic acid can be used in such anamount as capable of converting at least all of enalapril into itsmaleate salt, that is, in an amount equimolar with or larger thanenalapril. In case of an embodiment wherein enalapril maleate isdissolved in an aqueous liquid, maleic acid is present in an amountequimolar with enalapril.

The operation temperature for preparing an aqueous liquid having a pH ofat least 4 and containing enalapril, maleic acid and a base is notparticularly limited, since according to the process of the presentinvention a high temperature is not particularly required in obtaining asolution with a high concentration and the dissolution can be achievedin high concentrations even at a relatively low temperature.Practically, the operation can be made usually at a temperature of nothigher than 70° C., preferably not higher than 60° C., more preferablynot higher than 50° C., and at a temperature that the solvent does notfreeze. In particular, the operation can be suitably made at atemperature of about 20 to about 40° C. The same operation temperatureas above is also applicable to the embodiment wherein the solution isprepared by dissolving enalapril maleate.

Enalapril maleate can be crystallized in a high yield by mixing theaqueous liquid having a pH of at least 4 and containing enalapril,maleic acid and a base in high concentrations with an acid to lower thepH.

The acid is used in an amount capable of converting substantially all ofthe base in the aqueous liquid into a neutral salt. By such an amount ofan acid, all enalapril is turned to the maleate salt and the pH of theaqueous liquid becomes a pH in the vicinity of the pH that enalaprilmaleate itself has. This pH is generally from 2 to 3 and maximizes theamount of crystals deposited. The use of an acid in an amount largerthan the above is not always preferable, since the crystallized maleatesalt is converted into a salt with the acid used to be dissolved again,thus resulting in decrease of the amount of crystals. Also, the use ofan acid in an amount smaller than the above is not always preferable,since in many cases enalapril is not crystallized as the maleate salt toremain in the aqueous liquid, thus lowering the amount of crystalsdeposited.

The acid to be used is not particularly limited, but a strong acid ispreferred from the viewpoint of practical use. In particular, it isadvantageous to use a combination of a base with an acid which canenhance the salting out effect of the neutral salt formed with the baseused. From such a point of view, a mineral acid such as hydrochloricacid, sulfuric acid or phosphoric acid is preferable. Also, from theviewpoints of economy and easiness in treating waste water, hydrochloricacid and sulfuric acid are more preferable, and hydrochloric acid is themost preferable. Maleic acid can also be suitably used for this purpose.The acids may be used alone or in admixture thereof. Also, the acids maybe used as they are or may be diluted with an aqueous liquid to use inthe form of a solution.

Preferable combinations of base and acid are a combination of sodiumhydroxide and hydrochloric acid and a combination of potassium hydroxideand hydrochloric acid.

The operation temperature for crystallizing enalapril maleate by mixingthe above-mentioned aqueous liquid with an acid is not genericallyspecified, since it varies depending on the composition of the aqueousliquid, the operation manner and the like. Practically, thecrystallization is carried out at a temperature which is below theboiling point of the aqueous liquid and that the aqueous liquid does notfreeze. Although the temperature is not required to unnecessarilyelevate to a high temperature, the crystallization at a highertemperature provides the crystals with desirable characteristics such asexcellent filterability and drying property of the crystals andexcellent removability of impurities. From such a point of view, theoperation temperature is preferably from 40 to 70° C., more preferablyin the vicinity of 60° C. After conducting the crystallization operationat such a temperature, the aqueous liquid is finally cooled to atemperature of not more than 20° C., preferably not more than 10° C.,whereby the amount of crystals can be increased.

In general the mixing of the aqueous liquid and an acid can be practicedby adding the acid to the aqueous liquid having a pH of at least 4 andcontaining enalapril, maleic acid and a base, but a manner of adding theaqueous liquid to an acid is also adaptable. In particular, the lattermanner can be suitably used also from the viewpoint that when theaddition operation is practiced at a higher temperature, impartment ofheat to the solution until the maleate salt is crystallized out can bedecreased.

In the mixing operation, the time for adding all of the acid or theaqueous liquid is generally at least ¼ hour, preferably at least ⅓ hour,more preferably at least ½ hour. There is no limitation in the upperlimit of the addition time, but the addition time is generally at most20 hours, preferably at most 10 hours, more preferably at most 5 hours,from the viewpoints of productivity and the like.

In the operation for crystallizing enalapril maleate out of the aqueousliquid, it is also an important factor for increasing the amount ofcrystals deposited that the salting out effect of a neutral salt formedfrom the base and the acid present in the aqueous liquid, particularlythe salting out effect of an inorganic salt, can be effectivelyutilized. The concentration of the inorganic salt in the aqueous liquidcannot be generically specified since it varies depending on theconcentration, temperature and manner in crystallization operation andthe kind of the inorganic salt. However, it is important in promoting agood crystal growth not to excessively raise the concentration ofinorganic salt during the growth. In general, the concentration of theinorganic salt is at most 15% by weight, especially at most 10% byweight, and usually a concentration of 3 to 8% by weight is preferable.The process of the present invention is also advantageous in that by theoperation of mixing the aqueous liquid and the acid, the concentrationof inorganic salt is favorably increased as the crystallization of themaleate salt proceeds. Although the concentration of inorganic salt isinevitably increased and finally a sufficient salting out effect isobtained, an additional inorganic salt may be added as occasion demands.The salting out effect of an inorganic salt such as sodium chloride orpotassium chloride is particularly excellent.

The crystals of the maleate salt deposited can be easily taken out in ahigh yield by a simple operation such as filtration without any specialoperation. The use of an aqueous liquid as a solvent in the aboveoperations is advantageous also in that upon obtaining the maleate saltof enalapril (I), contamination of the product with the inorganic saltcoexisting in the system can be effectively minimized without applyingany special treatment.

The practice of the above process in an aqueous liquid is alsoadvantageous in that by-production of a diketopiperazine derivative ofthe formula (II):

can be effectively restrained in a series of operations. Further, thepurification according to the above process is also effective forremoval of N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline of theformula (III):

which is well known as an impurity produced by hydrolysis of theethoxycarbonyl group of enalapril, and the content thereof in theobtained enalapril maleate can be decreased to a negligible level. Likethis, enalapril maleate having a low content of these impurities can beeffectively obtained in a high yield and a high quality in a simplemanner.

The present invention is more specifically explained by means of thefollowing examples, but it is to be understood that the presentinvention is not limited to these examples.

In the examples, the purity and the contents of carboxy derivative (III)and diketopiperazine derivative (II) were measured by HPLC anddetermined by an absolute calibration method. The measurement conditionsof HPLC are as follows:

Column: FINEPAK SIL C18-5 (trade mark, 4.6 mm×25 cm, product of NipponBunkoh Kabushiki Kaisha)

Solvent: 0.1M KH₂PO₄ (pH 2.8)/CH₃CN (70:30 by volume)

Flow rate: 1.0 ml/minute

Temperature: 45° C.

Detection condition: UV 210 nm

EXAMPLE 1

To 200 ml of H₂O kept at 20° C. was added 56.2 g (0.114 mole) ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate saltcontaining 0.2% by weight of carboxy derivative (III). The maleate saltwas dissolved in water by adding 32.1 g (0.241 mole) of a 30% by weightaqueous solution of NaOH to this mixture with stirring to adjust to pH6.0±0.5. To the resulting solution was added dropwise 25.1 g (0.241mole) of conc. hydrochloric acid over 2 hours to adjust to pH 2.3'0.5,and the solution was then cooled to 0° C. over 4 hours. The resultingprecipitate was filtered and washed twice with 70 ml of cold water keptat a temperature of 0 to 3° C. The obtained wet crystals were driedunder vacuum (20 to 50° C., 30 mmHg→1 mmHg) to give 51.0 g (yield 91%)of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleatesalt. The purity was not less than 99%, and the content of each ofcarboxy derivative (III) and diketopiperazine (II) was not more than0.05% by weight.

EXAMPLE 2

To 120 ml of H₂O kept at 30° C. was added 33.0 g (0.067 mole) ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate saltcontaining 0.2% by weight of carboxy derivative (III). The maleate saltwas dissolved in water by adding 18.1 g (0.136 mole) of a 30% by weightaqueous solution of NaOH to this mixture with stirring to adjust to pH6.0±0.5. The resulting solution was heated to 60° C., and thereto wasadded dropwise 14.3 g (0.137 mole) of concentrated hydrochloric acidover 2 hours to adjust to pH 2.3±0.5. The mixture was then cooled to 0°C. over 4 hours, and thereto was added 12.0 g of NaCl and the stirringwas further continued for 2 hours. The resulting precipitate wasfiltered and washed twice with 40 ml of cold water kept at a temperatureof 0 to 3° C. The obtained wet crystals were dried under vacuum (20 to50° C., 30 mmHg→1 mmHg) to give 30.4 g (yield 92%) ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt.The purity was not less than 99%, and the content of each of carboxyderivative (III) and diketopiperazine (II) was not more than 0.05% byweight.

EXAMPLE 3

To 180 ml of H₂O kept at 30° C. was added 59.7 g (0.121 mole) ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate saltcontaining 0.2% by weight of carboxy derivative (III). The maleate saltwas dissolved in water by adding 32.4 g (0.243 mole) of a 30% by weightaqueous solution of NaOH to this mixture with stirring to adjust to pH6.0±0.5. The resulting solution was added dropwise to 44.4 g (0.244mole) of a 20% by weight aqueous solution of HCl kept at 60° C. over 4hours to adjust to pH 2.3±0.5, and was then cooled to 0° C. over 3hours. The resulting precipitate was filtered and washed twice with 70ml of cold water kept at a temperature of 0 to 3° C. The obtained wetcrystals were dried under vacuum (20 to 50° C., 30 mmHg 1 mmHg) to give55.2 g (yield 92%) ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt.The purity was not less than 99%, and the content of each of carboxyderivative (III) and diketopiperazine (II) was not more than 0.05% byweight.

EXAMPLE 4

To 155 ml of H₂O kept at 40° C. was added 59.7 g (0.121 mole) ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate saltcontaining 0.2% by weight of carboxy derivative (III). The maleate saltwas dissolved in water by adding 16.2 g (0.122 mole) of a 30% by weightaqueous solution of NaOH to this mixture with stirring to adjust to pH5.2±0.5. The resulting solution was added dropwise to 46.7 g (0.121mole) of a 30% by weight aqueous solution of maleic acid kept at 60° C.over 1 hour to adjust to pH 2.5±0.5, and was then cooled to 0° C. over 4hours. The resulting precipitate was filtered and washed twice with 70ml of cold water kept at a temperature of 0 to 3° C. The obtained wetcrystals were dried under vacuum (20 to 50° C., 30 mmHg→1 mmHg) to give56.2 g (yield 94%) ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt.The purity was not less than 99%, and the content of each of carboxyderivative (III) and diketopiperazine (II) was not more than 0.05% byweight.

EXAMPLE 5

To 200 g (0.1 17 mole) of a 22% by weight aqueous solution ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate saltcontaining 0.2% by weight of carboxy derivative (III) kept at 20° C. wasadded 13.8 g (0.119 mole) of maleic acid over 1 hour, while graduallyadding a 30% by weight aqueous solution of NaOH to keep the pH at6.2±0.5. The amount of the 30% by weight aqueous solution of NaOHrequired in this operation was 34.3 g (0.257 mole). The obtainedsolution was added dropwise to 47.1 g (0.258 mole) of a 20% by weightaqueous solution of HCl kept at 60° C. over 6 hours to adjust to pH2.3±0.5, and was then cooled to 0° C. over 3 hours. The resultingprecipitate was filtered and washed twice with 70 ml of cold water keptat a temperature of 0 to 3° C. The obtained wet crystals were driedunder vacuum (20 to 50° C., 30 mmHg→1 mmHg) to give 52.4 g (yield 91%)of N-(1(S) -ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleatesalt. The purity was not less than 99%, and the content of each ofcarboxy derivative (III) and diketopiperazine (II) was not more than0.05% by weight.

COMPARATIVE EXAMPLE

To 400 ml of water was added 24.4 g (0.050 mole) ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate saltcontaining 0.2% by weight of carboxy derivative (III), and it wasdissolved in water by heating at 60° C. (pH 2.5±0.5). The obtainedsolution was cooled to 0° C. over 4 hours with stirring, and was furtherstirred for 2 hours. The resulting precipitate was filtered and washedtwice with 30 ml of cold water kept at a temperature of 0 to 3° C. Theobtained wet crystals were dried under vacuum (20 to 50° C., 30 mmHg→1mmHg) to give 17.8 g (yield 73%) ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt.The purity was not less than 99%, and the content of each of carboxyderivative (III) and diketopiperazine (II) was not more than 0.05% byweight.

Industrial Applicability

According to the process of the present invention, enalapril maleatehaving a high quality can be crystallized out of an aqueous liquid in ahigh yield in a simple manner. That is to say, according to the processof the present invention, enalapril maleate can be purified toeffectively remove impurities such as carboxy derivative (III), whileadvantageously suppressing by-production of diketopiperazine derivative(II).

What is claimed is:
 1. A process for crystallizing a maleate salt ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline of the formula(I):

which comprises mixing an aqueous liquid having a pH of not less than 4and containing N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline(I), maleic acid and a base with a sufficient amount of an acid toconvert substantially all of said base into a neutral salt.
 2. Theprocess of claim 1, wherein based onN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (I), at leastequimolar amount of said maleic acid and at least equivalent amount ofsaid base are present in said aqueous liquid having a pH of not lessthan
 4. 3. The process of claim 1, wherein said aqueous liquid having apH of not less than 4 is prepared by dissolving a maleate salt ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (I) in anaqueous liquid kept at a pH of not less than 4 with said base.
 4. Theprocess of claim 1, wherein said mixing is carried out by adding saidacid to said aqueous liquid to convert said base into a neutral salt. 5.The process of claim 1, wherein said mixing is carried out by addingsaid aqueous liquid to said acid to convert said base into a neutralsalt.
 6. The process of any of claims 1 to 5, wherein said base is analkali metal hydroxide.
 7. The process of any of claims 1 to 5, whereinsaid acid is a mineral acid.
 8. The process of claim 7, wherein saidmineral acid is hydrochloric acid.
 9. The process of any of claims 1 to5, wherein said acid is maleic acid.
 10. The process of any of claims 1to 5, wherein said maleate salt is crystallized out while mixing saidaqueous liquid and said acid at a temperature of 40 to 70° C.
 11. Theprocess of any of claims 1 to 5, wherein the pH of said aqueous liquidafter the completion of mixing with said acid is from 2 to
 3. 12. Theprocess of any of claims 1 to 5, characterized by crystallizing amaleate salt ofN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (I) having alow content of N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline of theformula (III):

out of an aqueous liquid having a pH of not less than 4 and containingN-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (I), maleicacid and a base, while suppressing by-production of a diketopiperazinederivative of the formula (II):